Injury to articular cartilage is common; one study of 31,516 knee arthroscopies found that 63% of patients had at least one chondral injury present at the time of surgery, irrespective of their surgical indication (1). Cartilage injuries of the knee affect approximately 900,000 Americans annually, resulting in more than 200,000 surgical procedures (2). These injuries are frequently associated with pain, diminished joint functionality, and reduced quality of life. Due to the tissue's lack of intrinsic healing ability, traumatic joint injuries are often followed by formation of poorly repaired cartilage defects that lead to the early onset of osteoarthritis, which requires eventual joint replacement. Joint replacement, especially at a relatively young age, results in significant limitations to lifestyle, as well as potential complications. More importantly, joint replacement in a young patient group is complicated by the limited lifespan of the implants and the eventual requirement for revision surgery (3).
Articular cartilage is an avascular tissue that has no intrinsic capacity to heal or repair because of the lack of chondrocytic precursor cells. Surgical reparative techniques to repair cartilage injuries include marrow stimulation or microfracture, cell-based restorative techniques, and osteochondral allografts and autografts (2). Despite the refinement and advancement of these surgical techniques, full-thickness chondral defects still remain a major challenge, because none of the surgical methods, including the cell-based approaches, form hyaline cartilage. Thus, the common term used in the literature is ‘hyaline-like’ repair tissue. Since the function of articular cartilage is intrinsically linked to its structure, the benefits, characteristics and durability of this ‘hyaline-like’ cartilage tissue remains unknown. Currently, the two most common procedures being used to repair cartilage are the microfracture technique and the implantation of autologous in vitro expanded chondrocytes into the cartilage defect (2). The microfracture technique relies on the stimulation of the bone marrow to release mesenchymal stem cells that migrate into the lesion site, where these precursor cells differentiate into articular chondrocytes that produce an extracellular matrix that restores cartilage. Unfortunately, these precursor cells differentiate into fibro-chondrocytes that make fibrocartilage, a tissue with inferior biochemical and biomechanical properties compared to hyaline cartilage. Consequently, this intervention is reasonably successful in the short- and mid-terms (months to a few years) but fails in the long-term (2). In Mithoefer's systematic review of 28 clinical studies, a significant deterioration in outcomes was noted to be present two years following microfracture, secondary to the limited amount of hyaline cartilage that forms following the procedure (28). Autologous chondrocyte implantation has been shown to lead to the formation of a more hyaline-like cartilage structure, which is still far from being hyaline cartilage and therefore the successful long-term outcome of this type of approach is also questionable. In addition, this procedure is markedly more costly than the microfracture technique, requires open surgery instead of arthroscopic surgery, and involves two surgical procedures (4). The first surgery involves a cartilage tissue biopsy from a non-weight bearing area, while the second surgery is the actual repair surgery. Chondrocytes can be isolated from the harvested cartilage tissue biopsy and expanded in vitro (4). Expansion of chondrocytes in vitro is challenging and problematic, since these cells often dedifferentiate into a fibroblast-like phenotype in culture (5). In addition, this procedure involves the suturing of a collagen I/III bilayer to the border of the articular cartilage lesion, into which a suspension of autologous chondrocytes is then injected. A recent study has shown that suturing of articular cartilage induces severe local damage that is progressive and reminiscent of that associated with the early stages of OA (6). Therefore, the improvement or development of novel procedures or the identification of novel biological factors that prevent fibrocartilage formation and promote the formation of hyaline cartilage are highly warranted.
Hyaluronan (HA) is a key macromolecular component of the joint synovial fluid that provides viscoelastic protection and lubrication of the cartilage surfaces (7-9). In osteoarthritis (OA), HA can be degraded to lower molecular weight HA fragments, providing less effective shock absorption and lubrication (10) A leading approach to treatment of OA is intra-articular injections of high molecular weight HA. Injected HA provides analgesia over a period of weeks or months, despite the fact that the soluble HA is washed out of the joint within a few days. Hyaluronan preparations containing chemically cross-linked HA gels are also used for prolonged residence in the joint, with similar symptomatic relief. The prolonged effect in both cases suggests a favorable but temporary modification of processes that lead to pain. These HA therapeutic preparations are not truly disease modifying, and invasive joint replacement surgery remains the ultimate treatment (11-15).